tbuckley/cabot-search huggingface dataset:
TMIC-72. INVESTIGATING THE ROLES OF PGE2 IN MODULATING THE GBM-GAM MICROENVIRONMENT
Authors: Pin-Yuan Chen, Jian-Ying Chuang, An-Chih Wu, Wen-Bin Yang, Wen-Chang Chang, Ai-Yun Lin
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM), the most aggressive and deadliest primary brain tumor, is characterized by being surrounded by up to approximately 40% macrophages, which promote tumor progression through interactions with tumor cells. The mechanisms underlying how GBM and its associated macrophages (GAM) communicate remain not fully understood. In this study, we investigated the essential roles of Prostaglandin E2 (PGE2), which affects multiple functions of immune cells, in modulating the GBM microenvironment, specifically the GAM. Massive PGE2 accumulated in the GBM-GAM co-culture microenvironment, and the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) involved in PGE2 synthesis was markedly elevated in GAM. GAM expressed two PGE2 receptors, namely EP2 and EP4, and their expressions positively correlated with PTGS2 expression. Ingenuity pathway analysis (IPA) of differentially expressed (DE) genes obtained from GBM- (conditioned medium) CM-treated THP-1 macrophages revealed significant enrichment in biological functions associated with migration and proliferation. THP-1 macrophage migration promoted by GBM-CM was interrupted by blocking EP4 receptors using an antagonist. GBM-CM promoted THP-1 macrophages proliferation and increased proliferative enhancers, such as PI3KCD, AKT3, ETS1, and BHLHE41, while decreasing proliferative repressors, including MAF, MAFB, and CDKN1A. Cytokine array analysis indicated that GBM-CM shaped GAM into an immunosuppressive phenotype and elevated IL-6 secretion to promote GBM growth. In conclusion, our current results suggest that PGE2 accumulates in the GBM microenvironment, sustaining the macrophage population through increased recruitment and elevated local proliferation and shaping macrophages into an immunosuppressive type. Blockage of the PGE2 autocrine regulation, thus interrupting the supportive roles of GAM in GBM progression, may provide a novel therapeutic strategy for treating patients with GBM.
RADT-40. FINAL RESULTS OF THE PROSPECTIVE PHASE 2 MARCIE TRIAL: EFFICACY AND TOXICITY OF POSTOPERATIVE BIMODAL RADIOTHERAPY WITH C12-BOOST IN PATIENTS WITH ATYPICAL MENINGIOMAS FOLLOWING SUBTOTAL RESECTION
Authors: Maximilian Deng, Felix Hinz, Christian Karger, Philipp Sievers, Tanja Eichkorn, Eva Meixner, Juliane Hörner-Rieber, Jonathan Lischalk, Katharina Seidensaal, Christine Jungk, Andreas Unterberg, Antje Wick, Wolfgang Wick, Andreas von Deimling, Felix Sahm, Denise Bernhardt, Stephanie Combs, Klaus Herfarth, Jürgen Debus, Laila König
Journal: Neuro-Oncology (2023)

Abstract Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.
INNV-25. PROLONGED FOLLOW-UP OF AN OLIGODENDROGLIOMA PATIENT WITH HISTORY OF TUMOR TREATING FIELDS (TTF) AS POST CHEMO-RADIATION MAINTENANCE THERAPY
Authors: Uvin Ko, Beverly Dan Fu, Joon Myung, Xiao-Tang Kong
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: Recurrence of low and high-grade gliomas are common after radiation and chemotherapy. Despite continued research on glioma’s management, there is limited knowledge regarding the role of maintenance treatment after standard radiation and chemotherapy therapy. Tumor Treating Fields as maintenance therapy after radiation and chemotherapy may potentially help prevent recurrence of oligodendroglioma. Case Report: A 35-year-old male developed headaches and a non-enhancing mass was detected on his brain MRI in 2011. Observation was advised by his surgeon. The patient presented with seizures in early 2014, and his brain MRI found the mass developed new enhancement. In late 2014, the patient had multiple seizures, and significant progression of the tumor was discovered. The patient underwent craniotomy and biopsy in the middle cerebral artery distribution area in early 2015. Pathology reported grade II oligodendroglioma; however, a biopsy might have missed the high-grade glioma region. His brain MRI showed a significant enhancing lesion, which was clinically also consistent with grade III oligodendroglioma due to rapid growth. Radiation was conducted followed by 6 cycles of PCV chemotherapy throughout 11 months. Post-radiation-chemotherapy brain MRI was stable with a moderate size residue tumor at the right insula region. Following patient wishes, NovoTTF-100A, or Optune, was administered 6 weeks after completion of chemotherapy as maintenance therapy for 2 years to prevent tumor progression. Now, after 5 years being off Optune, the patient is full-functional, and his brain MRI is stable without tumor progression. Discussion: Our case highlights the potential effect of Tumor Treating Fields as maintenance therapy after initial radiation and chemotherapy for lower and higher grade oligodendrogliomas. The patient had rapid tumor progression on brain MRI prior to treatment and only underwent a biopsy without resection, yet uncommonly, remains survival and full functional since initial image diagnosis 12 years ago and tissue diagnosis 8 years ago.
IMMU-13. DEVELOPMENT OF ADAPTIVE IMMUNE RESISTANCE IN A MURINE GLIOMA MODEL TREATED WITH DENDRITIC CELL VACCINATION AND PD-1 CHECKPOINT BLOCKADE
Authors: Gilbert Herrera, Lu Sun, Alessandro Sammarco, Kelly Kennewick, Steven Bensinger, Robert Prins
Journal: Neuro-Oncology (2023)

Abstract Immunotherapies such as immune checkpoint inhibitors and active vaccination have shown great potential in unleashing antitumor immunity for cancer treatment. However, their effectiveness in treating glioblastoma (GBM) is limited. In a preclinical glioma model, administration of both autologous tumor lysate-pulsed dendritic cell vaccination (ATL-DC) and anti-PD-1 checkpoint blockade (aPD1) significantly increased survival and enhanced intratumoral T cell activation. We hypothesize that the combination of these two treatments will substantially increase the abundance and activity of tumor-reactive cytotoxic T cells. As such, we recently started a phase I trial administering ATL-DC and neoadjuvant aPD1 to recurrent GBM patients (NCT ID: NCT04201873). To understand the local antitumor immune response in greater depth, we performed single-cell RNA sequencing analysis of the CD45+ immune compartment of explanted gliomas from twelve mice, four of which were treated with ATL-DC and aPD1 while the other eight received no treatment. We found that the combination therapy increased tumor-infiltrating T cells, monocytes and DCs. We also observed the expansion and differentiation of CD8+ effector T cells under the effect of combination therapy. These T cells exhibited a differentiation trajectory from a Tcf7+Il2ra+ early activated phenotype to a terminally exhausted state marked by high expression of Pdcd1, Tox and Tigit. Interestingly, combination therapy specifically increased a macrophage subset that overexpressed Ch25h, an interferon-stimulated gene encoding for the oxysterol lipid 25-hydroxycholesterol (25-HC). Preliminary results from in vitro studies demonstrated that 25-HC restricted T cell proliferation and tumor cell cytolysis, suggesting its immunosuppressive function. In summary, our study reveals the impact of ATL-DC + aPD1 combination therapy on the immune microenvironment of GBM and a potential maladaptive mechanism mediated by 25-HC. Future studies will seek to exploit these targets therapeutically to develop more effective GBM treatment regimens.
CNSC-28. CELLULAR AND FUNCTIONAL REMODELING OF HUMAN CEREBRAL ORGANOIDS BY GLIOBLASTOMA STEM-LIKE CELLS
Authors: Sanjay Singh, Bojana Milutinovic, Lawrence Bronk, Julianna Bronk, Andrew Shepherd, David Grosshans, Lynette Phillips, Frederick Lang
Journal: Neuro-Oncology (2023)

Abstract The burgeoning field of cancer neuroscience focuses on deciphering the role of normal neural cells in brain tumor growth. Until recently, representation of normal human neural cells in brain tumor model systems was lacking. By utilizing human induced-pluripotent stem cells derived cerebral organoids (COs) co-cultured with glioblastoma stem-like cells (RFP-luciferase tagged MDA-GSCs, n = 3 representing each glioblastoma molecular sub-type), we investigated the effects of GSCs on CO-derived neural cells and their activity. COs and CO+MDA-GSCs were subjected to single-cell RNA-sequencing (scRNA-seq). As per typical micro-anatomy of COs, neural stem/progenitor cells are interiorly distributed whereas differentiated neurons are positioned on the surfaces, enabling measurement of neuronal action potential on surfaces of COs by micro-electrode arrays (MEA). The scRNA-seq data from CO+MDA-GSC samples were subset into CO-derived (luciferase-ve) and GSCs-derived (luciferase+ve). Compared with COs, co-cultured samples had significantly higher percentage of non-telencephalon neural progenitor cells (ntNPCs) (CO_vs._CO+MDA-GSC(luciferase-ve): 15.6% vs. 47.2%-63.4%) while the percentages of cortical NPC (cNPCs) and intermediate progenitors (IPs) was lower (CO_vs._CO+MDA-GSC(luciferase-ve): 39.2% vs. 12.0%-20.5%). These alterations in NPC/IPs abundance were accompanied by decreased proportions of cortical excitatory neurons (CO_vs._CO+MDA-GSC(Luciferase-ve): 33.2% vs. 7.9%-23.4%). Among luciferase+ve MDA-GSCs-derived cells in co-culture samples, mesenchymal MDA-GSCs had higher abundance of ntNPCs versus cNPCs (30.4% versus 63.6%) whereas, among classical and proneural MDA-GSCs ntNPCs were 11.45-22.8 times higher. Interestingly, 14.9% of proneural MDA-GSCs derived cells displayed inhibitory neuron signatures. After 3 weeks, the mean firing rate measured by MEA was significantly lower in co-cultures compared to COs (CO_vs._CO+MDA-GSC: 0.052 Hz vs. 0.0081 Hz p-value 0.000219), suggesting functional remodeling. Our results show that cellular remodeling of normal cells resulted in progenitor-like cell-state whereas that of MDA-GSCs varied across molecular sub-type. These results suggest interactions between normal and tumor cells can potentially be leveraged to manage brain tumor growth and its impact on normal brain.
INNV-03. INSTITUTION SPECIFIC CLINICAL TRIAL MATCHING WEB APPLICATION FOR CENTRAL NERVOUS SYSTEM METASTASES
Authors: Marissa Gilbert, Simeng Zhu, Mira Shah, Salim Siddiqui, Lisa R Rogers, Farzan Siddiqui
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Current clinical trials evaluating treatment options for patients with brain metastases are tailored to a number of clinical factors, including type of underlying cancer, number of brain metastases, size and volume of brain metastasis, prior treatment, and genomic characterization. A multidisciplinary brain metastasis tumor board was established at our institution in January 2023. Subsequently, an institution specific clinical trial matching web application was developed in-house to screen and match subjects for trials accruing at our institution. METHODS We reviewed our institution’s list of phase III surgical, radiation, and medical oncology clinical trials specific for brain metastasis to identify the most discriminating inclusion criteria that can be used as a basis for branching and differentiation. These disease specific trials were then individually assessed according to these criteria and these results were populated in a common separated value (CSV) file. RESULTS A web application was created using Python for analysis of the CSV and incorporating branching logic. HTML, CSS, and JavaScript were used for building the webpage interface. The web application is hosted on our institutional server and can be utilized to search available clinical trials for each patient being presented during tumor board. CONCLUSION We developed an institution specific web application that can be used to screen patients for various clinical trials. By developing this application and hosting it internally, we are able to edit the components at our discretion. The methodology for this web-build can be applied to other disease sites or institutions. This web application is useful for screening our institution’s clinical trial portfolio to identify potential gaps, and can also be used to avoid competing trials. This web application significantly reduces the time to identify protocol eligibility and has increased clinical trial enrollment.
EPID-21. EPIDEMIOLOGY AND CLINICOPATHOLOGICAL FEATURES OF MENINGIOMA PATIENTS: FINDINGS FROM NATIONAL BRAIN CENTER HOSPITAL INDONESIA
Authors: Yuli Felistia The, Nadira Fildza Amanda, Nugroho Harry Susanto, Sardiana Salam, Diorita Prayanti, Viola Maharani, Chairunnisa Baziad, Silvia Francina Lumempouw, Muhammad Miftahussurur
Journal: Neuro-Oncology (2023)

Abstract BACKGROUNDS Meningioma is considered as one of high prevalence disease, eight cases per 100.000 population, among intracranial tumours. This study aimed to assess the epidemiology and clinicopathological features of meningioma patients. METHODS This is a retrospective cohort study of hospitalized meningioma patients, excluding spinal meningioma, in National Brain Hospital, Jakarta, Indonesia between 2020 and 2022. Patient’s characteristics, symptoms, MRI results before surgery, and MRI results after surgery were obtained from medical records. Chi-square test, Fisher’s exact test, and logistic regression analysis performed with p-value &amp;lt; 0.05 was considered as significant. RESULTS We analysed 325 patients between 2020 and 2022, which number increases per year. Meningioma grade I was predominant than grade II and III, however grade II and III patients were slightly older than grade I patients (mean age 47.6 ± SD 13.7 years and 46.9 ± 10.3 years, respectively). The majority of patients were females than males with 4 to 1 ratio. The most common locations of brain meningioma were convexity (26.8%), followed by parasellar (11.7%), and falx (34%). Preoperative clinical symptoms in the form of muscle weakness (p=0.04), vision problem (p=0.02), hearing impairment (p=0.006), slusrred speech (p=0.003), and ptosis (0.01) were significantly related to more severe meningioma grading. However, in multivariable logistic regression only hearing impairment was significantly related with meningioma grading with odds ratio 0.313 (95% CI 0.113-0.869, p=0.02). CONCLUSIONS Meningioma prevalence alarming rise should get more attention. Especially as this tumor usually occurs productive age population. Clinical symptoms are associated with the severity, however further study is needed to support our finding.
EXTH-56. CSF PENETRATION COMPARISON OF TWO ORAL FORMULATIONS OF APL-101 IN A PRE-CLINICAL NON-HUMAN PRIMATE MODEL
Authors: Natalia Corvalan Cabanas, Cynthia Lester McCully, Cody Peer, Andrea Gross, John Glod, William Figg, Priya Shankarappa, Katherine Warren, Brigitte Widemann
Journal: Neuro-Oncology (2023)

Abstract Vebreltinib (APL-101) is a potent c-Met inhibitor which has shown efficacy in murine pre-clinical models and is under clinical trial evaluation for several cancer types, including adult high-grade glioma. The capsule formulation (APL-101-Cap) was reformulated as a pill (APL-101-Pill) with the expectation of increasing bioavailability. We determined and compared the plasma pharmacokinetics (PK) and cerebrospinal fluid (CSF) penetration of APL-101-Cap and APL-101-Pill in a non-human primate (NHP) model. METHODS: Seven animals, previously developed as serial CSF access models, were utilized across all studies. One NHP was studied with both formulations. Both formulations were administered orally as a single drug/single dose in serial studies, followed by serial plasma and CSF sample collections from 0-96 hours. Dosages: APL-101-Cap 3.25 mg/kg (n = 3) or 6.5 mg/kg (n = 4) and APL-101-Pill 5 mg/kg (n = 4). The resulting plasma concentrations from each formulation were quantified by LC-MS/MS. PK parameters were calculated via noncompartmental methods, and results were analyzed to assess CNS penetration (AUCCSF:AUCPlasma) and compare formulations. RESULTS: Mean (range) for plasma and CSF PK exposure [AUCLAST (hr*ng/mL)] reported. APL-101-Cap plasma exposure, regardless of dose, was more variable than APL-101-Pill. APL-101-Pill had lower exposure in both plasma (AUC 1893.0 (841-2865)] and CSF [AUC 27.7 (5.0-65.0)] than APL-101-Cap regardless of dose [(3.25 mg/kg): plasma AUC 9621.0 (1331-23132) and CSF AUC 688.0 (24-1352); 6.5 mg/kg: plasma AUC 6208.0 (1424-19800) and CSF AUC 606.0 (34-1179)]. CNS penetrance was higher with APL-101-Cap (3.2% [0.5-5.8%] at 3.25mg/kg; 4.2% (2.4-6%) at 6.5 mg/kg), but also more variable when compared to APL-101-Pill (1.2% [0.6-2.3%]). For APL-101-Cap, one animal at 3.25 mg/kg and two animals at 6.25 mg/kg had undetectable CSF concentrations. CONCLUSION: In this NHP model, single-dose oral administration of APL-101-Pill resulted in lower, but less variable plasma and CSF exposure compared to APL-101-Cap. APL-101-Cap CSF exposure was unaffected by dose escalation.
CTNI-68. PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR TARGETING GLIOBLASTOMA CANCER STEM CELLS
Authors: Yoshitaka Narita, Makoto Ohno, Chifumi Kitanaka, Shota Tanaka, Yukihiko Sonoda, Kazuhiko Mishima, Eiichi Ishikawa, Ken Ohashi, Motoo Nagane
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation (Stem Cells Transl Med. 2012;1(11)). We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Patients and METHODS Patients between 20 and 74 years of age with supratentorial GBM were eligible. MF dose-escalation study was performed using a 3 + 3 design as phase I part to determine recommended phase II dose. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. After completing phase I study, we proceeded to phase II part. RESULTS The first three patients were treated with 1,500 mg/day MF from 2021 and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2 (Cancers (Basel). 2022;14(17)). Based on the phase I study, we proceeded to phase II study with 2,250 mg/day MF from April 2022 and finished recruiting patients for phase II part in May 2023. Primary endpoint of phase II trial is progression-free survival rate at 12 months compared to historical data. CONCLUSION MF dose of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. We report the safety and efficacy of MF with TMZ for GBM.
EPCO-33. H3K4 METHYLATION IS A PREREQUISITE OF CELL FATE CHANGE DURING IDH-MUTANT GLIOMAGENESIS
Authors: Marilin Koch, Minh Deo, Sevin Turcan, Michael Hoetker, Christel Herold-Mende, Wolfgang Wick
Journal: Neuro-Oncology (2023)

Abstract RATIONALE: Low grade gliomas (LGGs) are defined by isocitrate dehydrogenase (IDH)-mutations that mediate broad epigenetic changes. However, additional determinants of low-grade gliomagenesis remain unknown, including factors necessary for the activation of LGG gene programs. Here, we aim at identifying epigenetic prerequisites of IDH-dependent gliomagenesis by modulating key chromatin modifiers in a conditionally IDHR132H-expressing immortalized human astrocyte (IHA) model system. METHODS: Using chemical compounds, we targeted key histone modifications and DNA methylation in an inducibly IDHR132H expressing IHA cell line. Flow cytometry for the LGG-associated marker L1CAM served as a primary read-out. Compound candidates were further assessed with RNA-Seq and mass spectrometry. Phenotypic evaluation included sphere formation, clonogenicity, cell viability and invasion assays. Relevant findings were additionally assessed in established LGG cell lines TS603, NCH612 and NCH1681. RESULTS: L1CAM was significantly altered by DOT1L inhibitor EPZ00477, MLL1 inhibitor MM-102, and EZH2 inhibitor GSK-126. MM-102 treatment was associated with broad transcriptional downregulation. Intersecting data from MM-102 and GSK126 treated cells, we identified potential bivalent genes directly affected by inhibitor treatment that were enriched for Wnt signaling and developmental transcription factors implicated in gliomagenesis. Overlapping transcriptional and proteomics data, MM-102-treated cells exhibited a signature of predominantly downregulated genes associated with invasion/migration, extracellular matrix (ECM) and cholesterol metabolism. Fittingly, cells showed impaired invasion, clonal proliferation and sphere forming capacity. The negative effect on sphere formation tracked inversely with aggressiveness of established LGG cell lines. CONCLUSION: Interfering with histone H3K4 methylation through MLL1 inhibition is associated with broad downregulation of gene sets related to cell identity and ECM/migration, reflected by disruption of clonal proliferation in IDHR132H astrocytes and LGG cell lines. This points to deposition of H3K4 methylation as a prerequisite of cell fate change in LGG development. Persisting effects on established LGG cell lines warrant its investigation as a potential therapeutic target.